Cancer is a term which is used to describe the development of abnormal cells which grow in a rapid and uncontrolled manner and are often invasive. The invasion of vital organs frequently results in the death of a patient.
Cancer is extremely widespread and, indeed, it is thought that about 30% of people are likely to contract cancer at some time in their lives with cancer being the cause of death in around 20%. Traditional treatments for cancer include surgery and radiotherapy but, more recently, attention has been turned to the development of chemotherapeutic or cytotoxic agents which can damage or kill cancer cells.
In recent years, increasing attention has been drawn towards the occurrence of tissue changes that are indicative of an increased risk for the subsequent development of particular cancers at that site of change. A variety of these have been described, including modifications of the intestinal wall (intestinal polyps) which are associated with increased incidence of cancers of the colon and rectum, alterations of the skin (actinic keratoses) which are associated with carcinomas of the skin, and condylomata of the cervix, which are associated with cancer of the uterine cervix. To one skilled in the art, these conditions or tissue changes tending to proceed to cancer, to be associated with the development of cancer, or to carry a significant risk of cancer are known as precancerous conditions or lesions. In some cases, the cause of these precancerous conditions is reasonably well established, as in the case of actinic keratoses resulting from excessive exposure to sunlight, or infection with human papilloma virus in the case of condylomata of the cervix (Cancer in Practice by G J G Rees, S E Goodman and J A Bullimore. Pub Butterworth-Heinemann, Oxford, 1993). In other cases, the cause of the precancerous lesion has not been identified.
The present invention relates to the use of certain muramyl peptide compounds (MDPs) in the prophylaxis of cancer and especially in the treatment of precancerous lesions.
It has long been known that non-specific stimulation of the immune system can be brought about by exposure to bacteria, or components extracted from bacterial cells. The specific components responsible for this activity were identified as sugar-containing peptides of the cell wall, and further biochemical analysis of the peptides identified them as the peptidoglycan component of the cell wall. The smallest effective synthetic molecule was found to be an N-acetyl-muramyl-L-alanyl-D-isoglutamine (Merser et al, Biochem. Biophys. Res. Comm. 66 1316 (1975)) which is often referred to as a prototype muramyl dipeptide or prototype MDP.
Subsequently, a wide variety of analogues of prototype muramyl dipeptide were synthesised, some of which have been proposed as treatments for the restoration of immune function or the non-specific stimulation of the immune system. These analogues, and prototype MDP itself are known as muramyl peptide compounds (MDPs).
In the past, some work has been carried out on the use of MDPs in the treatment of cancer and, for example, Key et al, J. Natl. Cancer Inst., 69(5), 1189-1198 (1982) describe the treatment of lung melanoma metastases with liposomes containing an MDP derivative. Later, the same group of workers investigated the optimal conditions and limitations for the eradication of melanoma metastases using a liposome encapsulated MDP derivative, MTP-PE (Fidler et al, Cancer Imnunol. Inmmunother., 21(3) 169-173 (1986)). In addition it was found that orally administered non-liposome encapsulated MTP-PE produced tumouricidal activity in both lung and peritoneal macrophages and was effective in inhibiting lung and lymph node metastasis although it was not effective in eradicating well established melanoma metastases (Fidler et al, J. Immunol., 138(12), 4509-4514 (1987)).
Phillips et al, J. Biol. Response Modif., 6(6), 678-691 also describe work relating to the treatment of experimental pulmonary metastases using liposomes containing lipophilic MDP analogues. Again, the compounds were used to treat experimentally induced pulmonary B16 melanoma tumours in mice. However, Kleinerman et al in J. Clin. Oncology, 9(2), 259-267 (1991) concluded that it is unlikely that the MDP derivative L-MTP-PE can serve as a single modality in treating metastatic disease.
Some MDPs have been used in clinical trials for human therapy. For example, Kleinerman et al (Kleinerman, E S, Cancer Immunol. Immunother, 34: 211-220, 1992) have used a lipophilic analogue in a liposomal formulation in the treatment of lung metastases developed in patients with osteosarcoma.